Safety, Tolerability, and Efficacy of Darexaban (YM150) in Patients With Acute Coronary Syndrome - RUBY -1

Description:

Darexaban is a novel oral factor Xa inhibitor, and has been shown to be effective in the treatment of venous thromboembolism (VTE). The current trial was a phase II trial designed to evaluate the safety and tolerability of different doses and dose regimens of darexaban on top of standard treatment (aspirin with or without clopidogrel) in the secondary prevention of ischemic vascular events in patients with recent acute coronary syndrome (ACS).

Hypothesis:

Darexaban on top of standard treatment (aspirin with or without clopidogrel) would be safe and effective in the secondary prevention of ischemic vascular events in patients with recent ACS.

Study Design

  • Randomized
  • Parallel

Patient Populations:

  • Age ≥18 years old
  • Diagnosis of STE-ACS or NSTE-ACS (within one other risk factor for ischemic events) as index event
  • Elevated cardiac biomarkers (troponin T or I, or creatine kinase-myocardial band)
  • Clinically stable and receiving current standard oral antiplatelet therapy
  • Able to be randomized within 7 days after presentation

    Number of screened applicants: 1,370
    Number of enrollees: 1,279
    Duration of follow-up: 26 weeks
    Mean patient age: 59.5 years
    Percentage female: 15%
    Ejection fraction: <35% (58%)
    NYHA class: I (33%), II (53%), III (14%)

Exclusions:

  • Need for ongoing anticoagulant therapy, thrombolytics, glycoprotein IIb/IIIa antagonists, or other antiplatelet drugs
  • Patient scheduled for invasive procedures with potential for bleeding within 60 days
  • Active bleeding or high risk of bleeding during the study
  • Recent stroke or transient ischemic attack <12 months prior to index event
  • Persistent systolic blood pressure of ≥160 mm Hg and/or diastolic blood pressure of ≥100 mm Hg at baseline
  • Hepatic insufficiency or alanine transaminase >2.0x the upper limit of normal (ULN) or total bilirubin >1.5x the ULN
  • Renal creatinine clearance <60 ml/min

Primary Endpoints:

  • Incidence of major and/or clinically relevant nonmajor bleeding events, during the 6 months of double-blind treatment (defined using a modified International Society on Thrombosis and Hemostasis [ISTH] definition)

Secondary Endpoints:

  • Major bleeding events according to the TIMI bleeding definition
  • Composite of all-cause mortality, nonfatal MI, nonfatal stroke, and severe recurrent ischemia

Drug/Procedures Used:

Patients with recent ACS (within 7 days) were randomized to receive in a 1:1:1:1:1:1:1 fashion either placebo or darexaban 5 mg BID, 10 mg QD, 15 mg BID, 30 mg QD, 30 mg BID, or 60 mg QD.

Concomitant Medications:

Aspirin was used at a dose of 75-325 mg daily, as per local practice. The lower dose range of aspirin (75-81 mg/day) was recommended, or clopidogrel 75 mg/day if aspirin was contraindicated or not tolerated, or a combination of aspirin 75-325 mg and clopidogrel 75 mg daily. Other medications were: statins (95%), beta-blockers (92%), angiotensin-converting enzyme inhibitors (78%), and proton pump inhibitors (34%).

Principal Findings:

A total of 1,279 patients were randomized, and 1,258 constituted the full analysis set. Of these, the respective sample sizes for placebo and the escalating doses of darexaban were 319, 159, 159, 159, 156, 153, and 153. Baseline characteristics were fairly similar between the composite darexaban (n = 939) and placebo arms. About 22% had diabetes mellitus, 13% had prior myocardial infarction (MI), 3% had prior stroke, and 4% had known peripheral vascular disease. The majority of patients presented with ST-segment elevation MI (71%), and percutaneous coronary intervention was undertaken in about 74% of all patients. The mean Global Registry of Acute Coronary Events (GRACE) score at presentation was 132.8. About 97% were on dual antiplatelet therapy (DAPT) during the study.

The primary endpoint of major and clinically relevant nonmajor bleeding at 6 months demonstrated a dose-response relationship for darexaban, with higher bleeding noted in the BID regimens for the same dose (3.1% for placebo vs. 6.8% vs. 5.6% vs. 7.5% vs. 5.6% vs. 11.3% vs. 7.3%; p = 0.009). The pooled bleeding rates were higher with darexaban, as compared with placebo (hazard ratio 2.23, 95% confidence interval 1.13-4.6; p = 0.022). Similarly, any bleeding and any Thrombolysis In Myocardial Infarction (TIMI) were also increased in a dose-dependent manner. The composite efficacy outcome at 6 months noted numerically higher event rates for darexapan as compared with placebo (4.4% for placebo vs. 3.8% vs. 3.8% vs. 6.3% vs. 6.4% vs. 5.9% vs. 7.8%; p > 0.05).

All adverse events, including liver toxicity, were similar between the two arms.

Interpretation:

The results of the current phase II trial indicate that darexaban is associated with a dose-related increase in bleeding as compared with placebo in patients with ACS already on DAPT. There is no evidence of improved efficacy for ischemic endpoints; indeed, event rates were numerically higher in the darexaban arm, especially the higher doses, as compared with placebo.

Darexaban is a novel oral anti-Xa anticoagulant, with a mechanism of action similar to other agents such as rivaroxaban and apixaban. While they have shown efficacy is settings such as VTE and atrial fibrillation, all of them have demonstrated a similar dose-dependent increase in bleeding in ACS patients with no or slim evidence of benefit for ischemic endpoints (i.e., rivaroxaban in ATLAS ACS-TIMI 46, apixaban in APPRAISE-1 and -2). However, this was a phase II trial, and will need phase III trials (especially of the low-dose regimens) to specifically test for efficacy.

References:

Steg G, Mehta SR, Jukema JW, et al., on behalf of the RUBY-1 Investigators. RUBY-1: a randomized, double-blind, placebo-controlled trial of the safety and tolerability of the novel oral factor Xa inhibitor darexaban (YM150) following acute coronary syndrome. Eur Heart J 2011;Aug 30:[Epub ahead of print].

Presented by Dr. Ph. Gabriel Steg at the European Society of Cardiology Congress, Paris, France, August 2011.

Clinical Topics: Acute Coronary Syndromes, Anticoagulation Management, Dyslipidemia, Invasive Cardiovascular Angiography and Intervention, Prevention, Pulmonary Hypertension and Venous Thromboembolism, Vascular Medicine, Atherosclerotic Disease (CAD/PAD), Anticoagulation Management and ACS, Anticoagulation Management and Venothromboembolism, Lipid Metabolism, Novel Agents, Interventions and ACS, Interventions and Vascular Medicine

Keywords: Myocardial Infarction, Acute Coronary Syndrome, Stroke, Morpholines, Thiophenes, Venous Thromboembolism, Ticlopidine, Pyrazoles, Azepines, Peripheral Vascular Diseases, Percutaneous Coronary Intervention, Registries, Secondary Prevention, Liver, Confidence Intervals, Factor Xa, Benzamides, Pyridones, Diabetes Mellitus


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